Novel strategies for radioresistant head and neck cancers through targeting the DNA damage response in combination with high-precision proton beam the

通过靶向 DNA 损伤反应并结合高精度质子束，治疗抗辐射头颈癌的新策略

• 批准号: 2600797
• 金额: --
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2600797
• 关键词: Novel; strategies; radioresistant; head; neck

Proton beam therapy (PBT) is increasingly being utilized worldwide for the treatment of specific cancers, such as head and neck squamous carcinoma (HNSCC), as it precisely delivers the radiation dose to the tumour and limits irradiation of surrounding normal tissues. However, there are still significant biological uncertainties of the molecular/cellular effects of PBT due to decreases in energy (increases in ionisation/linear energy transfer) at and around the Bragg peak where the radiation dose is deposited. This consequently leads to significant uncertainties in the use of PBT for the treatment of cancer patients in the clinic. Furthermore, identification of combinational strategies using drugs/small molecule inhibitors that can enhance sensitivity of radioresistant cancers, including subtypes of HNSCC, to PBT are unclear and which maybe distinct from conventional (x-ray) radiation.This MRC-funded DTP studentship will develop novel PBT research investigating key enzymes involved in the cellular DNA damage response (including PARG, ATM, ATR and DNA-Pk), as targets to overcome radioresistance of HNSCC. This will be delivered through the use of established 2D cell lines, 3D spheroids and patient-derived organoids of HNSCC. This project has high translational potential in the establishment of more effective clinical management and treatments for HNSCC patients using PBT.

质子束治疗（PBT）在全球范围内越来越多地用于治疗特定癌症，如头颈部鳞状细胞癌（HNSCC），因为它精确地将辐射剂量输送到肿瘤并限制周围正常组织的辐射。然而，由于在辐射剂量沉积的布拉格峰处及其周围的能量降低（电离/线性能量转移增加），PBT的分子/细胞效应仍然存在显著的生物学不确定性。因此，这导致在临床中使用PBT治疗癌症患者的显著不确定性。此外，使用药物/小分子抑制剂的组合策略，可以提高放射抗性癌症（包括HNSCC亚型）对PBT的敏感性，目前还不清楚，可能与常规（x射线）辐射不同。这个MRC资助的DTP学生奖学金将开发新的PBT研究，调查参与细胞DNA损伤反应的关键酶（包括PARG、ATM、ATR和DNA-Pk）作为克服HNSCC放射抗性的靶点。这将通过使用HNSCC的已建立的2D细胞系、3D球状体和患者来源的类器官来实现。该项目在使用PBT建立更有效的临床管理和治疗HNSCC患者方面具有很高的转化潜力。